Microbiological cultures and antimicrobial prophylaxis in patients undergoing total pancreatectomy with islet cell autotransplantation

Kristen R Szempruh , Anne M Lhiewiz , Brittney M Willims , Amn Kumr ,Xvier Bldwin , Chirg S Desi ,*

a Pharmacy Department, University of North Carolina Medical Center, Chapel Hill, NC, USA

b Division of Infectious Disease, University of North Carolina Medical Center, Chapel Hill, NC, USA

c Department of Surgery, Transplant, University of North Carolina Medical Center, Chapel Hill, NC, USA

TotheEditor:

Total pancreatectomy with islet cell autotransplantation (TPIAT)is a viable treatment option upon failed endoscopic and medical therapy for patients with chronic pancreatitis.This procedure involves surgical removal of the entire pancreas, isolation of islet cells and re-infusion of these cells into the liver via portal vein [ 1 , 2 ].The risk of contamination to the final islet cell product can occur at several stages of the isolation procedure [3].In order to ensure the sterility of the islet cell product, multiple samples from the preservation and cannulation solution, and the final islet cell product are sent for bacterial cultures.Prior studies have found variable clinical consequences of these cultures on infectious complications or graft function [3-9].Herein we aimed to determine the incidence of infection in 60 days post-TPIAT and its association with the culture data.

All patients undergoing TPIAT between February 2018 and August 2021 at University of North Carolina Medical Center were analyzed.The surgery was performed using the previously described technique [10].The isolation procedure included washing the pancreas with a ciprofloxacin solution.If the total tissue volume was more than body weight × 0.25 mL/kg, purification was performed to remove connective tissue and acinar cells.The final islet cell product was analyzed by gram stain, endotoxin, and viability.The concentration was measured in EU/mL for endotoxin,and the threshold was 5 EU/kg of patient’s body weight.For viability, we assessed a total of 50 islets, and they were assessed by the sum of all observations divided by the total number of assessed islets.The viability threshold was equal to or greater than 70%.The product was transfused into the portal vein via splenic vein stump with the details described previously [11].For all patients, samples of preservation and cannulation solutions and the final islet cell product were shipped to an outside testing lab for aerobic and anaerobic bacterial and fungal cultures using BacT/Alert system.The product was released based on gram stain results, which were tested at the institution’s microbiology lab.

Prior patient culture data were not routinely reviewed before TPIAT as their primary care was outside our center, but no patients were known preoperatively to be colonized with multidrugresistance organisms or to have had recent candidal infection.Patients who had endoscopic retrograde cholangiopancreatography(ERCP) performed at our institution did not have cultures obtained given the absence of cholangitis.

The antimicrobial prophylactic regimens are listed in Table 1 and were all initially given intravenously.The variety of regimens were due to drug shortages and drug allergies.The typical duration of antimicrobial prophylaxis was from 30 min prior to incision until 7 days postoperatively.

Table 1Demographics characteristics of patients with TPIAT ( n = 22).

The primary study outcome was incidence of infection within 60 days post-TPIAT.Secondary outcomes included the association of islet cell culture findings with infections and incidence of adverse effects of antimicrobial prophylaxis.Demographic and clinical outcomes were descriptive and reported as percentages.

Twenty-two patients met inclusion criteria.The average postoperative hospital stay was 13 days.Two patients (9.1%) had detection of microorganisms within 60 days of surgery.Two patients (9.1%)hadC.difficilecolitis treated with oral vancomycin for 10 days on postoperative day (POD) 22 and POD 37, respectively.

One patient with multiple preoperative comorbidities and postoperativeC.difficlecolitis also developed multiple postoperative intra-abdominal fluid collections without an enteric leak.On POD 53, he presented with abdominal abscess at the site of prior drain placement.Purulent aspirate culture obtained on POD 59 was notable for 2 + growth ofCandidaalbicans,susceptible to both fluconazole and micafungin, and he was treated with fluconazole for two weeks.This candidal infection was attributed to peritoneal contamination from prior drain placement rather than to the TPIAT itself.

Eight patients (36.4%) had at least one positive culture from islet cell product, but only two (9.1%) had all three cultures positive.Five patients (22.7%) had a positive preservation solution culture, four (18.2%) had a positive cannulation solution culture, andsix (27.3%) had a positive final islet cell product culture.The organisms from each culture are shown in Table 2.None of the six patients with positive final islet cell product cultures had a gastrointestinal procedure, such as ERCP with or without stent placement or removal 60 days prior to TPIAT.Four patients had islet cell products requiring purification; however, none of these had positive cultures.Only one patient with a positive culture had been diagnosed with diabetes prior to TPIAT.

Table 2Microbiological speciation and susceptibilities.

Five of the six patients with islet cell product cultures positive for bacteria were treated with amoxicillin/clavulanic acid after completing prophylaxis.One of these patients had a fever between completing prophylaxis and starting treatment, but the others remained asymptomatic.One patient withC.albicansin the islet cell product culture was treated with fluconazole for 7 days after completing prophylaxis.No patient with a positive islet cell product culture developed an infection with the corresponding organism.

The median duration of antimicrobial prophylaxis for all patients was 7 days (range: 2-10).The median duration of therapy for additional antimicrobials was 5 days (range: 3-7).Antimicrobial use is further described in Tables 1 and 2.One episode of acute kidney injury was attributed to the combination of vancomycin and piperacillin-tazobactam.Vancomycin was dosed appropriately with therapeutic drug monitoring.Patient was on vancomycin for less than two days and was discontinued when the renal function worsened.The serum creatinine increased from a baseline of 0.76 mg/dL and reached 6.1 mg/dL.Fortunately, the patient did not require dialysis and the serum creatinine later returned to baseline.

In this study positive islet cell cultures were not associated with any infections postoperatively.Preservation and cannulation solution took place prior to the isolation and sterilization of the islet cells and did not appear to present an effect on clinical outcomes.Our study supports the notion neither of these cultures would be needed; however, they are standard practice and are required for allogenic islet cell transplant.The majority of postoperative infections in prior studies were unrelated to the final islet culture results [ 3 , 12 ].Our positive final islet cell cultures rate of 36% and infections complications rate of 9.1% were lower than those reported in other studies, where rates were roughly 61%-89% for positive islet cell culture and 14%-29% for infectious complications rate [ 8 , 12 ].One larger study found 22% of those with infectious complications also had a positive final islet cell product [8].

However, the antimicrobial choice and duration of prophylaxis to effectively reduce infectious complications without causing unwanted harm remain undecided.Most guidelines recommend less than 24 h of perioperative antimicrobial prophylaxis and for pancreaticoduodenectomy, cefazolin and fluconazole (if high risk for fungal infection) are mentioned [ 13 , 14 ].Goł ˛ebiewska and colleagues extended antibiotic duration from 24 h to 7 days in 4 of 22 patients due to contamination of the islet cell product, but still had an overall 50% infectious complication rate [15].The use of broader antibiotics and various durations have been reported [ 3,13-15 ].At our institution, anti-inflammatory agents, anakinra and etanercept, are used to reduce the inflammation associated with the instant blood-mediated reaction.These agents have the potential to increase the patient’s risk of infections as previously described [16].

The majority of organisms that grew were ofStreptococcusspp.and were likely covered with our standard perioperative prophylaxis regimen.Other studies have found that most final islet cell cultures were positive for gram positive bacteria [ 4 , 5 ].The growth of anaerobes in the final culture of No.4 patient suggests empirical anaerobic coverage is also warranted perioperatively.The growth ofCandidaspp.in final islet products has been found between 6%-21% in some studies, but its clinical relevance is debatable [ 4 , 5 ].We added antifungal prophylaxis afterC.albicansgrew from a final islet cell product.Narrowing our anti-fungal prophylaxis from micafungin to fluconazole coverage may be appropriate based on our results.Additional questions exist regarding the need for methicillin-resistantStaphylococcusaureus(MRSA) prophylaxis.Staphylococcusaureus(SA) growth in TPIAT cultures has been reported as high as 47%-51%, which suggests an agent to cover at least methicillin-susceptible SA is needed [ 4 , 5 ].Perhaps knowing MRSA colonization or nasal MRSA screening prior to surgery could assist in predicting need for MRSA prophylaxis [17].

Prolonged, broad-spectrum antimicrobial prophylaxis and treatment based on islet cell culture results may have minimized the number of infectious outcomes in our study but was coupled with antimicrobial-associated adverse events.Penicillins,cephalosporins, and fluoroquinolones pose a higher risk forC.difficile[18].Additionally, the combination of vancomycin and piperacillin/tazobactam (TZP) resulting in acute kidney injury has been documented along with the nephrotoxicity associated with vancomycin [ 19 , 20 ].

Limitations of our study include the sample size and variety of antimicrobial prophylaxis regimens used.According to the Collaborative Islet Transplant Registry, a total of 819 auto-islet recipients have been reported between 1999 and 2015 [21].The majority of literatures on cultures and infectious outcomes have lower sample sizes, which implies the importance of further reporting additional cases.

In conclusion, due to broad spectrum antimicrobial prophylaxis,perioperative islet cell cultures were not associated with postoperative infections.However, shorter overall antimicrobial durations and/or more narrow coverage may reduce their associated risks.

Acknowledgments

None.

CRediT authorship contribution statement

Kristen R Szempruch:Conceptualization, Data curation, Formal analysis, Writing -original draft, Writing -review & editing.Anne M Lachiewicz:Data curation, Formal analysis, Writing -original draft, Writing -review & editing.Brittney M Williams:Data curation, Writing - review & editing.Aman Kumar:Data curation, Writing - review & editing.Xavier Baldwin:Data curation, Writing - review & editing.Chirag S Desai:Conceptualization, Data curation, Formal analysis, Writing - original draft, Writing - review & editing.

Funding

None.

Ethical approval

This study was approved by the Institutional Review Board (IRB#19-2591) of University of North Carolina Medical Center.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.